MicroRNAs as haematopoiesis regulators.
MicroRNAs (miRNAs) are 20-22 nucleotides long small noncoding RNAs that can bind to the 37UTR or 5,UTR or in ORF of target mRNA resulting in translational repression or mRNA degradation based on degree of homology. It is believed that miRNAs regulate gene expression in multicellular organisms, but miRNAs are also identified in unicellular algae Chlamydomonas reinhardtii . Interestingly it has been shown that miRNAs can activate the translation. miRNA-122 is specifically expressed in liver where; it plays vital role in fatty acid metabolism and enhances the replication of hepatitis C virus (HCV) RNA by binding to its 57UTR . 0rom et al. found that miR-10a binds to the messenger RNAs (mRNAs) encoding ribosomal proteins to enhance the translation of proteins and ribosomal biogenesis . Due to increase in cloning and computational approaches, there has been a tremendous increase in the number of newly found miRNAs. A total of 9169 miRNAs have been found in different species among which human genome codes for 1424 miRNAs . It has been found that 60% of the human mRNA contains miRNA binding sites. Each mRNA is targeted by many miRNAs conversely and each miRNA can target many mRNAs. miRNAs exhibit different characteristics in plants and mammals. In plants, miRNAs require perfect match with their target mRNAs, whereas in mammals miRNA complementarity covers 2-7 bases, also known as the seed region [6, 7]. In mammals, miRNA target sites are mostly in the 37UTR region and rarely in 57UTR and coding regions also, whereas, in case of plants target sites are mostly in the coding region. The mechanism by which a miRNA can diminish protein expression is unclear, but several proposals are there from different experimental evidences. miRNAs can interfere with translation process at the stage of initiation (Figure 2) or elongation (Figure 3), or target mRNA may be affected by isolating it from ribosomal machinery [8-10].
The experimental evidences indicate that miRNA regulates translation inhibition at initiation (Figure 2) or later stages of translation (Figure 3). Binding of eIF4E to the cap region of mRNA is the initiation of the assembly of the initiation complex; it is identified that miRNA interfere with the eIF4E and impairs its function and poly(A) tail function is also inhibited . There are other evidences suggesting that miRNAs repress translation at later stages of initiation. miRNA lin-4 target the lin-14 and lin-28 mRNAs, but under inhibitory conditions mRNAs of lin-14, lin-28 are not altered indicating that miRNAs inhibit translation after the initiation stage. Interestingly in both cap dependent and cap independent translation mRNAs are inhibited by synthetic miRNA suggesting postinitiation inhibition. Another mechanism by which miRNA inhibit translation is by ribosome drop off, in which ribosomes which are engaged in translation are directed to terminate translation prematurely (Figure 3(a)). There is other proposed mechanisms that miRNAs are degrading the nascent polypeptides by recruiting the proteolytic enzymes (Figure 3(b)) 12,13].
2. Biogenesis of miRNA
There are various proteins involved in miRNA biogenesis (Table 2). miRNAs are synthesised from coding or noncoding part of genes (promoter, introns, and exons) by RNA polymerase II into a precursor called pri-miRNA. The primiRNA is processed by the enzyme Drosha and cleaved into 70-120 nucleotides called precursor miRNA (pre-miRNA). The recombinant Drosha is unable to produce pre-miRNA suggesting that other cofactors maybe required for its action. DGCR8 an important cofactor is required for the processing of pri-miRNA and is believed to recognize the cleavage site between ssRNA and stem of pri-miRNA. It is approximately 11 base pairs away from the dsRNA-ssRNA junction . Interestingly some miRNAs are processed independent of Drosha to generate pre-miRNA from introns with the association of debranching enzyme and spliceosome . PremiRNA is exported from the nucleus to the cytoplasm  by Exportin-5 and it is processed to 19-22 nucleotide duplex by Dicer . Like Drosha, Dicer contains associated proteins TRBP, PACT which increases Dicer stability and activity. There are various isoforms of Dicer and the roles of these isoforms are not known [83, 84]. The mature miRNA then associates with a protein complex known as RNA induced silencing complex (RISC) at 37UTR or 57UTR or in ORF of target genes  (Figure 1). Complementarity between target mRNA and miRNA particularly in seed region is important in determining the miRNA target sites. The mechanism of miRNA mediated gene silencing is not clearly explored till now and it has been known that miRNA suppresses the expression of a gene by inhibiting the translation of its mRNA. Other major functions of the miRNA are removal of mRNA from translation machinery and associating it with processing bodies (P-bodies) where mRNA is degraded . It has been reported that miRNA association with mRNA degrades the mRNA through decapping and deadenylation of mRNA . Byrepressing the mRNAs, miRNAs are involved in gene expression changes leading to regulation of different biological aspects including proliferation, differentiation, apoptosis, immune response, ageing, and metabolism.
3. Detection of miRNA
miRNA detection enable us to study the regulation of miRNA in various biological processes. There are various methods to detect the mature forms of miRNA which include deep sequencing , microarrays , northern blot , and real-time PCR . In microarray analysis the first step is isolation of the total RNA which contains miRNA and here enrichment of small RNA enhances the sensitivity of the detection. This RNA is labeled and hybridized to designed probes specific for a miRNA and later studying the signal intensities we can measure the levels of miRNA in a sample. Microarray analysis can give the data of known miRNAs and it cannot be quantified, but it is useful to assess the miRNA in two different samples relatively. To find new miRNAs deep sequencing can be used, but it is not very established technique; it includes sequencing RNA and analyzing the folding properties and validating the data by northern blot or real-time PCR .
4. Prediction of miRNA Targets
Many studies indicate that deregulation of miRNAs results in various disorders including cancer, diabetes, metabolic disorders, and cardiovascular disorders, so understanding of miRNA regulation in various pathologies enables us to solve the diagnostic and therapeutic challenges. To understand the association of miRNA and mRNA many computational based databases have been developed which predict possible targets of miRNAs by using different algorithms (Table 3). All these tools recognize miRNA targets based on seed sequence of miRNA and 37UTR of target genes. Hence it becomes necessary to validate these targets by experimental approaches such as luciferase assay, RNA interference, microarray, pulsed (p) SILAC, and Argonaute HITS-CLIP [88-91]. The nomenclature of miRNA is a sequential process given in Table 1.
4.1. Ago HITS-CLIP. Genome-wide functional protein-RNA interaction sites on RNA can be identified by HITS-CLIP, high throughput sequencing of RNAs isolated by cross linking, and immunoprecipitation (Figure 4). In this method RNA and bound protein Argonaute are cross linked by ultraviolet light which gives Arg-miRNA and Arg-RNA binding sites. The remaining RNA is digested and then the RNA and RNA complexes are isolated by immunoprecipitation which are sequenced by next generation sequencers. Comparison of these two datasets helps us to know the miRNA target sites .
4.2. Microarray and qRT-PCR. miRNAs target the corresponding mRNA and reduce its stability by degrading it. miRNA target can be detected by overexpressing the miRNA in a cell line that does not express the miRNA. Comparison of control and miRNA overexpression in cell lines using qRT-PCR and microarray will enable the detection of miRNA target or its associated pathway .
4.3. SILAC. Baek et al. have shown the use of stable isotope labeling using amino acids in cell culture (SILAC) in the identification of miRNA targets . In this method proteins of the culture medium are labeled with radio-labeled amino acids. For the identification of miRNA targets SILAC method is slightly modified, instead of radio-labeled amino acid, and heavy isotope is added to the growth medium for short time to know the newly synthesized proteins. Heavy and medium heavy isotope signal intensities are measured, if the mRNA is the target of a miRNA, the heavy medium isotope signal intensity is decreased; otherwise there is no change in the intensities (i.e., normal and malignant tissue). Protein analysis by mass spectrometry combined with SILAC has strong correlation with miRNA activity  Figure 5).
5. Biological Roles of miRNA
miRNAs regulate several biological processes such as apoptosis, insulin secretion, lipid metabolism, stem cell differentiation, heart development, muscle differentiation, cardiomyocyte hypertrophy, antigen presentation, and ageing. In this section biological roles of miRNA are described briefly.
5.1. Apoptosis. Apoptosis is a regulated process of cell death necessary for normal development and homeostasis. Aberrant expression of miRNA leads to failure of apoptosis finally resulting in evolution of cancer. Even though the exact role of miRNA in the apoptosis is not well understood, there are several instances of its role in apoptosis. Cimmino et al. showed that miR-15 and miR-16 induce apoptosis by targeting Bcl2 , whereas miR-330 induces apoptosis in PC-3 cells by reducing the E2F1 mediated Akt phosphorylation . Interestingly, miR-21 acts as an antiapoptotic factor and its knockdown activates caspase activity and increased apoptotic cell death in glioblastoma cells .
5.2. Insulin Secretion. Diabetes is the most common metabolic disorder in the world. miRNAs have been found to be involved in the several physiological processes including glucose homeostasis. It was reported that some miRNAs are important for the release of insulin. miR-375 is essential for [beta]-cell survival, proliferation, and division. The expression level of transcription factor Onecut-2 was reduced, whereas the level of granuphilin was increased by miR-9 which is a negative regulator of insulin release . Surprisingly, knockdown of miR-24, miR-26, miR-182, or miR-148 in cultured [beta]-cells also resulted in reduced insulin mRNA level .
5.3. Lipid Metabolism. miRNAs have been shown to be important regulators of lipid metabolism also. miR-33 downregulates ABC transporters there by controlling the cholesterol efflux and HDL biogenesis. Decreased serum cholesterol levels were observed due to miR-122 inhibition and it has been shown that it maintains the hepatic cell phenotype [99, 100]. In addition, miR-33a is involved in the cholesterol export and [beta]-oxidation of fatty acids. Its inhibition leads to increased levels of HDL in mice 101,102].
5.4. Immunity. It has been reported that CD34+ hematopoietic stem cells express 33 miRNAs, among which miR-155 regulates both myelopoiesis and erythropoiesis . In ES (expand) cells, miRNAs regulate Sox2, Nanog, and Oct-4 pluripotency transcription factors . Theyplaymajor role in immunity where overexpression of miR-181a results in reduction in [CD8.sup.+] T cells and removal of Dicer in early B cell development leads to prevention of pre-B cell to proB cell transition [105, 106]. Liu et al. showed that miR-148 and miR-152 negatively regulate the antigen presentation of DCs and inhibited the production of cytokines . Antigen specific T-cell mediated immunity is suppressed by miR-155 and inhibition of miR-155 reversed this effect .
The production of different types of blood cells including their formation, development, and differentiation of blood cells is collectively known as haematopoiesis. Blood cells are divided into three lineages erythroid cells, lymphocytes, and myeloid cells. From many studies on miRNA expression including murine and hematopoietic system, it has been shown that miRNAs are not only involved in the normal haematopoiesis but also play a vital role in every stage of haematopoiesis. Dicer is an enzyme essential for miRNA biogenesis, whose deficiency leads to embryonic death and lack of stem cells in hematopoietic system . Pro-B cell to pre-B cell transition is blocked due to removal of Dicer in Bcell progenitors . T-cell development and differentiation is impaired in conditional deletion of Dicer and reduction in the number of [CD8.sup.+], CD [4.sup.+]T cells in thymus .
6.1. Megakaryopoiesis. From the hematopoietic stem cells through series of commitment steps megakaryocytes (MKs) are generated. MKs undergo a unique maturation process including megakaryoblast formation and polyploidization to produce proplatelets (Figure 6). Platelets are shed from these proplatelets into bone marrow sinusoids. Earlier studies have shown that miRNAs control the MK development and release of platelets (Table 4). Opalinska et al. studied miRNA expression in murine system where they examined 435 miRNAs among them 13 were upregulated and 81 were downregulated . Overexpressing the miR-155 in K562 cells decreased the differentiation of megakaryocyte and erythroid cells by regulating the targets Meis-1 and Ets-1 . The miR-34a contributes to MK differentiation by targeting cMyb, CDKs and it targets MEK1, thereby repressing proliferation [42,43]. Interestingly, miR-146a, miR-145 are involved in megakaryopoiesis by activating innate immunity targets TIRAP and TRAF6  which mediates the 5q syndrome phenotype . During megakaryocyte development increase in miR146a levels is repressed by PLZF transcription factor and its target CXCR4 . miR-150 favors the differentiation of megakaryocyte-erythroid progenitors into megakaryocyte lineage rather than erythroid lineage. TPO induces miR150 expression which in turn targets cMyb in TPO cells [47, 48]. It was detected in myeloproliferative neoplasm patient platelets that miRNA-28 is overexpressed which prevents megakaryocyte differentiation from CD34+cells by targeting TPO receptor . RUNX1 upregulates miR-27a by binding to it and miR-27a targets RUNX1 and decreases its levels and miR181a inhibit [Ca.sup.2+] induced differentiation and accelerates apoptosis [50,51]. LIN28is repressed by miR181, thereby interrupting the LIN28/let-7 and axis then let7 is upregulated; finally it promotes megakaryocyte differentiation identifying that miR-130 targets MAFB and miR-10a expression inversely correlate with HOX A1 in differentiated megakaryocytes [53,113].
6.2. Erythropoiesis. The term erythropoiesis refers to the process of production of red blood cells. In humans erythropoiesis occurs in red bone marrow. Kidneys respond to low levels of oxygen by releasing a hormone erythropoietin, which triggers erythropoiesis. It has been identified that certain miRNAs play crucial role in erythroid homeostasis (Figure 7). miR-144 and miR-451 are required for erythroid homeostasis (Table 5). Mice deficient of miR-144 and miR451 have shown to undergo impairment in late erythrocyte maturation which further leads to splenomegaly, mild anaemia, and erythroid hyperplasia. GATA1 controls the erythropoiesis through regulating the two conserved miRNAs, miR-451 and miR-144, which in turn regulate GATA1 expression . Defect in erythroid differentiation and reduction in hematocrit are observed in [miR-451.sup.-/-] mice. miR-451 upregulation rescued the defect in erythroid differentiation by targeting 14-3-3C . LMO2 is a transcriptional regulator which is important for HSC development and erythropoiesis. Blood formation is affected in mice lacking this gene and miR-223. LMO2 levels inversely correlated to this miRNA and transduction of miR-223 reduces the commitment of erythroid progenitors [57, 58]. miR-15b, miR-16, and miR22 have shown strong correlation with the erythroid surface markers CD36, CD235a, and CD71, whereas miR-28 was negatively correlated and CD71 transcriptional activities favour miR-320 in reticulocytes [59, 60]. miR-221, miR-222, and miR-24 inhibit normal erythropoiesis and miR-24 targets ALK4. cMyb and miR-15a are involved in the transition from BFU-E to CFU-E stage [61-63]. Fetal haemoglobin ([sigma]2 [gamma]2) is the crucial oxygen carrying protein from 2nd to 3rd trimester development stage which has been observed to be completely replaced by ([alpha]2 [beta]2) in adults. It was identified that miR-96 inhibits the [gamma]-globin gene expression, thereby repressing the erythropoiesis .
6.3. Mast Cells. Mast cells are resident cells of tissues throughout body and contain granules rich in histamine and heparin. Mast cells are bone marrow derived and their survival depends on stem cell factor. Biological roles of mast cells include wound healing, innate immunity defense against pathogens, and angiogenesis. miRNAs play important role in mast cells; for example, miR-221 is involved in the adhesion of mast cells, degranulation, and migration towards SCF (expand) and cytokine production . miR-126 favors mast cell proliferation and cytokine production by targeting Spred1. miR-221 and 222 are upregulated after mast cell activation; overexpression of these miRNAs causes defect in cell morphology and cell cycle regulation without affecting viability [116,117].
6.4. Myelopoiesis. Myelopoiesis is the formation of myeloid cells including granulocytes, monocytes, eosinophils, basophiles, and neutrophils. Many studies reported the role of miRNA in myelopoiesis and in myeloid malignancies. Eva et al. showed that miR-125b affects myelopoiesis in several ways and finally cause of blocking the G-CSF induced differentiation of granulocytes. They found that the Stat3 and Bak1 are the direct targets of miR-125b . AML1 regulates myelopoiesis by recruiting chromatin remodeling enzymes on pre-miR-223 gene and silencing cell differentiation . NF1-A negatively regulates granulocyte and monocyte differentiation. miR-223 and miR-424 repress NF1- A and these miRNA are activated by C/EBPa and PU.1, respectively. AML1 is known to be targeted by miR-17-5p-92 cluster, where this cluster is downregulated in monocytopoiesis and thereby AML1 is upregulated causing induction of M-CSF . Zinc finger protein growth factor independent-1 (Gfi-1) is essential for normal granulocyte differentiation. A mutation in GFI1 causes severe congenital neutropenia (SCN). miR-196B and miR-21 are downregulated in SCN and up- or down- regulation of these miRNAs severely affects myelopoiesis 121]. miR299-5p is involved in the [CD34.sup.+] progenitor cell regulation and also in the modulation of monocyte differentiation .
Granulocytes. Granulocytes are classified as basophils, eosinophils, and neutrophils based on their morphology and staining properties of their cytoplasm. Basophils are comprised of <1% of white blood cells and eosinophils 1-3% and neutrophils constitute 50-70% of white blood cells. Basophils are nonphagocytic and release certain pharmacologically active substances from their cytoplasmic granules which are involved in certain allergic reactions. These granulocytes have lobed nucleus, granular cytoplasm, and stains with methylene blue which is a basic dye. There are no reports on miRNA regulation of basophils but identified that miR-31, miR-107, and miR-222 are highly expressed in basophils .
Eosinophils. Eosinophils are motile phagocytic cells that can migrate from blood to tissue spaces. They have bilobed nucleus, granular cytoplasm and can be stained with compounds like eosin red, an acidic dye. Very few studies have been reported on the miRNA regulation of eosinophils. miR126 inhibition has been found to cause blockade of the recruitment of eosinophils at the airway walls in allergic asthma, which results in suppressing the development of airway disease . miR-935 is found to be upregulated in eosinophils (5.6 fold) compared to DCs. Inhibition of miR-145 suppresses the eosinophil inflammation and mucous secretion. On treating mice with anti-miR-145 and dexamethasone, a similar effect was shown by both reducing eosinophils infiltration and suppression of mucous secretion in air ways [125, 126]. Wong et al. reported that miR21* regulate the eosinophil apoptosis by enhancing GMCSF (expand) which activates and sustains the survival of eosinophils through ERK pathway. Inhibition of miR-21* diminishes its survival activity and activates apoptosis in eosinophils .
Neutrophils. Neutrophils are called as polymorph nuclear leucocyte and they have multilobed nucleus. The granulated cytoplasm can stain with both acidic and basic stains. After being produced in bone marrow these are released into the peripheral blood and circulate 7-10 hours after which these migrate into the tissues. miR-29B regulates the neutrophil differentiation and PU1, Myc are the transcriptional regulators of miR-29B . miR-223 is highly expressed in neutrophils and it plays a crucial role in granulocyte progenitor proliferation and function . miRNA clusters regulate apoptosis and survival of several cancers recently. Ward et al. showed that miRNA clusters are expressed in human neutrophils. miR-17-92 cluster (miR-17, miR-19a, miR19b, miR-20a, miR-92a, miR-18a, and miR-17*) contains seven mature miRNAs five of them (miR-17, miR-19a, miR19b, miR-20a, miR-92a) are expressed in human neutrophils, whereas miR-18a, miR-17* were not detected in human neutrophils. This suggests that these clusters may play a crucial role in regulating neutrophil functions . Proinflammatory signals upregulate miR-9 in neutrophils through NF-Th . Neutrophil elastase (NE), a serine protease, stimulates the secretion of mucus in pulmonary tracts by inducing MUC5AC. miR-146a negatively regulates the hypersecretion of the mucus by MUC5AC . After spinal cord injury miR-223 was upregulated and highly expressed after 12 hours. Immunohistochemistry revealed that this miR-223 observed in Gr-1 positive neutrophil which indicates that miR-223 regulates neutrophil after spinal cord injury . miR-133a and miR-1 are downregulated in myeloproliferative disorder neutrophils; these have also been reported previously in certain cancers . Radom-Aizik et al. showed the neutrophil miRNA expression pattern after exercise, interestingly 20 of 38 miRNAs downregulated immediately after exercise; remaining 18 miRNAs were upregulated. These miRNAs which were affected are regulating the genes that are involved in the apoptosis and immune processes .
Mononuclear Phagocytes. Mononuclear phagocytes are comprised of monocytes and macrophages and monocytes are present in blood and macrophages reside in tissues. In bone marrow granulocyte-monocyte progenitors differentiate into promonocytes and on entering the blood stream these mature into monocytes. After being circulated in blood for 8 hours these enlarge and enter into tissues and differentiate into tissue specific macrophages. MiRNAs have been found to play a crucial role in regulation of monocyte/macrophages. miR146a increases in monocytes/macrophages upon induction of LPS and it negatively regulates innate immune response as it targets TRAF6 which is involved in TLR signalling, this regulation is dependent on Relb [136, 137]. Pauley et al. showed that in Sjogren's syndrome miR-146a increases the phagocytic activity of monocytes and it suppresses the inflammatory cytokine production . On treating monocytes and U937 cell lines with LPS it was found that there is an upregulation of miR-525-5p and its putative target VPAC1 was shown to be down-regulated suggesting that miR-5255p regulates the control of immune homeostasis . miR124 has been found to have role in macrophage activation and its overexpression in bone marrow macrophages leads to inhibition of TNFa . In human monocytes, resveratrol increases miR-663 which target genes such as JunD and JunB decreasing the AP1 activity induced by LPS, hence altering the immune response . Sharbati et al. showed that miR-21, miR-222, miR-23b, miR-24, and miR-27a are upregulated in monocyte differentiation and miR-29 in monocyte infection which suggests that these miRNAs may regulate monocyte defence mechanisms through TGF-[beta] signalling .
T-Lymphocytes. T-lymphocytes belonging to white blood cells are produced in bone marrow and mature in thymus and express T cell receptors. T cell receptors recognize an antigen which is bound to major histocompatibility protein, a membrane protein by the process known as antigen presentation. When a T-cell recognizes an antigen which is bound to MHC on a cell it proliferates and differentiates into memory cell and effector cells (Figure 8). There are three subpopulations of T cells they are T helper cell (Th), T-cytotoxic cell (Tc), and T suppressor cell (Ts). T helper cells can be distinguished from T-cytotoxic cells based on the membrane protein CD4 and CD8, respectively. Like other biological processes regulated by miRNA T-cell development in thymus and their activation is controlled by miRNAs. Wu et al. studied the miRNA profiling of naive, effector, and CD8 memory T-cells and they found that miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b, and let-7f are upregulated sevenfold than other miRNAs. They also observed that miRNA expression in effector T-cells was down-regulated compared to naive T cells but their levels are restored back in memory T-cells, suggesting that miRNA may have important in regulation of T-cell development and differentiation . Proliferating T cells contain shorter 3'UTR compared to the normal cells due to which they have less miRNA targeting sites; hence proliferating cells are resistant to regulation by miRNA . Deletion of Dicer in T-cell lineage results in reduction in the number of Treg cells and its suppressor activity. Since Dicer is required for miRNA biogenesis and absence of Dicer is found to hinder in Treg cell development in thymus, it indicates that miRNAs are required for the T-cell development [145, 146]. miRNA-181a is involved in the T and B cell differentiation; the miRNA expression is found to be low in matured and peripheral T-cells, whereas it is highly expressed in the double positive T lymphocytes which are sensitive to low affinity peptide antigens, indicating that miRNA regulates the sensitivity of T-cell receptor . Virts and Thoman showed the age related expression of miRNA in thymopoiesis and they observed that 53% of miRNAs are upregulated in the aged TN1 cells . Ohyashiki et al. showed that miR92a reduced in [CD8.sup.+] T-cells progressively with age . miRNA-146a is upregulated, whereas miR-363, miR-498 are downregulated in rheumatoid arthritis CD4+ T-cells and miR-146a is involved in the suppression of apoptosis and play a role in rheumatoid arthritis pathogenesis . Almanza et al. showed that cell fate determination takes place based on the balancing effects of different miRNAs such as miR-150, the let-7, and miR-155 and they found that miR-150 targets KChIP which is upregulated in CD8 T-cell .
B Lymphocytes. B lymphocytes produced in the bone marrow as immature cells and migrate to the secondary lymphoid organs where they transformed into mature B cell. They express a membrane bound antibody, molecule called B-cell receptor. When a naive B-cell finds an antigen which matches its membrane bound antibody then it starts proliferating and they differentiate into memory B-cell and effector Bcell which produce antibody molecules. Antibodies are glycoproteins and they consist of two light chain polypeptides and two heavy chain polypeptides. Several observations suggest that the role of miRNA in B-cell development and function (Figure 9). Tan et al. studied the miRNA profiling of germinal center, memory, and naive B cells. They observed that several miRNAs are elevated in germinal center of Bcell, which include miR-106a, miR-181b, and miR-17-5p. miR150 is upregulated in all the three subsets and found that it is the target of survivin, cMyb which is critical for B Cell development and its premature expression inhibits the B- cell early development . These results suggest that miRNAs regulate B-cell maturation and development and very little is known about their regulation in B-cell. MiR-150 reduces the mature B cell levels in circulation but has little effect on myeloid lineage cells. It blocks the transition from pro-B cell to pre-B cell by targeting cMyb, which is crucial for the lymphocyte maturation . miR-155 is required for the BCell responses to both thymic dependent and independent antigens and the B-Cell which lacks miR-155 decreases in its response to antigen and production of high affinity IgG1 antibody; interestingly it has been found that miR-155 targets the PU1 transcription factor . miR-15 and miR-16 are deleted (13q14) or downregulated in most of the B-CLLs indicating their involvement in the pathogenesis of B-cell chronic lymphocytic leukemias . Chen et al. identified that miR-181 increase the B lineage cells suggesting that it may play a crucial role in B-cell differentiation .
7. miRNA in Haematological Malignancies
Haematological malignancies are malignant neoplasms that affect blood, lymph node, bone marrow, and other parts of the lymphatic system. These malignancies may arise from myeloid and lymphoid cell lineages lymphoma. Lymphocytic leukaemia and myeloma arise from lymphoid lineage cells, whereas AML, CML, and myelodisplastic syndromes arise from myeloid
lineage cells. Haematological malignancies account for 9.5% and lymphomas are more common than any other malignancies in the USA. Leukemias are classified into acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute monocytic leukemia (AMOL), and so forth. Lymphomas are classified into Hodgkin's lymphomas and non-Hodgkin's lymphomas . Expression profiles of miRNAs have shown that they are involved in the haematological malignancies.
7.1. Acute Myeloid Leukemia. Acute myelogenous leukemia is the most common type of leukemia in adults also known as acute myeloblastic leukemia, acute nonlymphocytic leukemia, and acute granulocytic leukemia and is a rapidly growing malignant neoplasm in which many WBCs are found in blood and bone marrow. In acute myeloid leukemia more immature cells are produced abruptly and progression is very fast. Many studies have shown deregulation of miRNAs in AMLs (Table 6). Li et al. showed that miR-126/126* upregulation is associated with chromosomal translocations and inhibited apoptosis and enhances cell viability and proliferation. They also observed that miR126 targets the tumour suppressor protein PLK2 (polo-like kinase2) which is involved in the cell cycle checkpoint . Transcription factor C/EBPa regulates miR-223 expression. miR-223 inhibits the cell cycle regulator protein E2F1 which leads to suppression of granulopoiesis. They also found that E2F1 binds to the miR-223 promoter in AML cells and blocks its expression indicating that E2F1 is a transcriptional inhibitor of miR-223 in AML. miRNA-221 has been shown to be overexpressed in several solid tumours and it is highly expressed in AML showing its significant role in oncogenesis. miRNAs are epigenetically deregulated in AML. miR-223 is silenced by the hypermethylation of its upstream elements . Cammarata et al. described the oncogenic role of miRNA-221 in AML and it has been found that it inhibits the CDK inhibitor p27 They also observed that the tumour suppressor miRNA let-7b is down-regulated in AML . C/EBPa is epigenetically silenced in AML, thereby blocking the myeloid differentiation and leads to leukemia. It was identified by computational approach that miR-124a target the C/EBPa . Hypoxia-inducible factor 1 (HIF-1) is also playing a crucial role in the miRNA signaling network by modulating the miR-20a and miR-17 which can inhibit the p21 . Garzon et al. suggested miR-29b as a tumour suppressor miRNA in AML. Its expression is low in AML restoration which leads to reduction in the tumorigenicity and have shown the relation between miRNA and DNA hypermethylation . miR-29b overexpression resulted in the reduced expression of DNA methyl transferases DNMT1, DNMT3B, and DNMT3A. ERG is an oncogene which is deregulated in AML and T-ALL. It has been shown that miR196a and miR-196b regulate the ERG mRNA; its aberrant expression indicates its role in AML . Protooncogene cKit overexpress in AML and it has been shown that miR193b is downregulated in AML and its overexpression resulted in downregulation of c-Kit. It clearly indicated that c-Kit is direct target of miR-193b and it may be therapeutic target in c-Kit positive AML cases .
7.2. Chronic Myelogenous Leukemia. Chronic myelogenous leukemia or chronic granulocytic leukemia is a neoplasm of blood cells especially myeloid cells in which uncontrolled growth of granulocytes (eosinophils, basophils, and neutrophils) is observed. This leukemia is characterized by Philadelphia chromosome translocation and it is a translocation between two chromosomes chromosome 9 and 22, it is denoted as t(9; 22)(q34; q11) . Due to this translocation BCR gene on chromosome 22 and ABL gene on chromosome 9 is fused and this fusion product of BCR-ABL protein is a tyrosine kinase. It causes genomic instability by inhibiting DNA repair and finally leads to accumulation of genetic abnormalities . Recently it has been shown that miR-203 inhibits the expression of BCR-ABL and thereby inhibited cell growth and colony formation. In another study it is shown that overexpression of miR-29b inhibited cell growth and colony formation by inhibiting ABL1 and BCR/ABL1 . Xu et al. showed the feedback regulation between BCR, BCR/ABL1, GATA1 and miR-138. In this study they demonstrated that overexpression of miR-138 represses BCR/ABL1 and CCND3 by binding to the coding and 37UTR regions, respectively . Interestingly, miR-138 expression is increased by GATA1, and repressed by BCR/ABL in addition to imatinib resistance in CML.Turrini et al. suggested that miRNA may play a role in imatinib distribution in CML therapy and they found that miR-212 increases the ABCG2 expression upon treatment with imatinib in CML . To study the pathology of CML it is essential to study the signaling pathways. Specific miRNAs miR-155, miR-564, and miR-31 are downregulated in CML and extrapolation of these results suggested that VEGF, mTOR, ErbB, and MAPK are the main signaling pathways related to the miRNAs . In a different study it was shown that miR-181a, miR-221, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-150, and miR-222 are downregulated in CML and the targets of these miRNAs are associated with EGFR, ERBB, TGFB1, MAPK, and p53 pathways . RalA is a downstream molecule of Bcr-Abl in Ras signalling pathway and is targeted by miR181a which plays an important role in CML . Bcr-Abl decreases the tumor suppressor miRNAs and increases the oncogenic miRNAs that leads to leukemic transformation. It was confirmed that knockdown of BCR-ABL results in reduction of miR-212, miR-425-5p, miR-130a, miR-130b and miR-148a. Interestingly, overexpression of these miRNAs is correlated with reduction in CCND3 suggesting that BCR-ABL induced oncogenic miRNAs are involved in the downregulation of CCND3 in CML . miRNAs which are involved in CML pathogenesis are described in Table 7.
7.3. Multiple Myeloma. Myeloma is a clonal B-cell malignancy characterized by the aberrant accumulation of plasma cells (PCs) within bone marrow (BM) and extramedullary sites [162,163]. Myeloma arises from the multifocal proliferation of long-lived PCs and, despite all available therapies, remains invariably fatal . Several studies have identified miRNAs that are deregulated during myelomagenesis, and subsequent studies have explored the role of miRNAs as diagnostics to detect disease or to monitor myeloma progression [165, 166]. These studies have found that the vast majority of miRNAs that are aberrantly expressed in MM cells are upregulated compared with their expression in normal PCs . Zhou et al. compared miRNA expression profiles (miREP) of 52 newly diagnosed MM patients with that obtained from PCs of two healthy donors. Among 464 miRNAs analyzed, 95 had a higher mean expression in PC samples of MM patients compared with those of healthy donors . In related studies, miRNA-15a was downregulated in relapsed and/or refractory MM and found to regulate tumor progression in MM cell lines (MMCLs) . Separately, it was found that miRNAs-15a and miRNAs16 expression levels were often elevated in the PCs from newly diagnosed MM patients in comparison with healthy PCs . The miRNA-17-92 cluster, which targets the apoptosis facilitator Bcl-2, was also reported to confer tumourigenicity in MM . miRNA-29b has been reported to downregulate Mcl-1 and to induce apoptosis of myeloma cells . The miRNA-193b-365 cluster is overexpressed in MM and three miRNAs-720, 1308, and 1246 were significantly higher in PCs of myeloma patients than healthy controls [166, 172]. HOX9, c-Myc, Bcl-2, and SHP1/SHP2 represent targets of miRNA-146b, 140, 145, 125a, 151, 223, 155, and Let-7f, and changes in expression of these miRNAs may be involved in myelomagenesis and associated with overall prognosis . miRNA-17-92 clusters are other pivotal miRNAs activated by Myc and are highly linked to the progression of MM. Gao et al. reported that in addition to miRNA-17-92 cluster expression; miRNA-15a and 16-1 are also linked to poor prognosis in MM patients . Those with elevated miRNA17, 20, and 92 levels had shorter progression-free survival than those with reduced miRNA levels. Higher miRNA-20a and 148a levels in myeloma patients are associated with a shorter relapse-free survival, to suggest a possible association between miRNA-20a and poor prognosis . Expression of miRNAs-153, 490, 455, 642, 500, and 296 is associated with a better event-free survival, whereas miRNAs-548d, 373, 554, and 888 expression correlates with a poorer outcome . The precise role of miRNAs in myeloma needs to be further elucidated, although they are predicted to be involved in PC growth, survival, growth factor response, homing, drug resistance, and BM interaction.
miRNAs are important regulators of haematopoiesis and control the gene expression of several transcription factors essential for the commitment, proliferation, differentiation, and apoptosis of hematopoietic stem cells. Hematological malignancies arise not only due to the aberrant expression of proteins but also by the regulators of the genes such as miRNAs. Deregulation of miRNA expression results in haematological malignancies. A single miRNA targets many genes and it is not clear whether targeting a single gene or multiple genes leads to hematological malignancies. miRNAs can function through several pathways which are involved in disease manifestations. Gain of function and loss of function experiments will give a better idea about the clinical use of miRNAs. In future more studies need to be focussed on the animal models for the consistent and reliable results which will enable us to understand the pathophysiology of haematological malignancies.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by DBT-IYBA, DBT-RGYI, DBTNIAB, DST, ICMR, UPE-UoH, and UGC grants of Government of India. The authors appreciate the funding in form of CSIR and UGC fellowships from Government of India.
 A. Molnar, F. Schwach, D. J. Studholme, E. C. Thuenemann, and D. C. Baulcombe, "miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii," Nature, vol. 447, no. 7148, pp. 1126-1129, 2007
 R. C. Lee, R. L. Feinbaum, and V. Ambros, "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14," Cell, vol. 75, no. 5, pp. 843-854,1993.
 A. Molnar, F. Schwach, D. J. Studholme, E. C. Thuenemann, and D. C. Baulcombe, "miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii," Nature, vol. 447, no. 7148, pp. 1126-1129, 2007
 C. L. Jopling, M. Yi, A. M. Lancaster, S. M. Lemon, and P. Sarnow, "Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA," Science, vol. 309, no. 5740, pp. 1577-1581, 2005.
 U. A. 0rom, F. C. Nielsen, and A. H. Lund, "MicroRNA-10a Binds the 5;UTR of ribosomal protein mRNAs and enhances their translation," Molecular Cell, vol. 30, no. 4, pp. 460-471, 2008.
 R. C. Friedman, K. K.-H. Farh, C. B. Burge, and D. P. Bartel, "Most mammalian mRNAs are conserved targets of MicroRNAs," Genome Research, vol. 19, no. 1, pp. 92-105, 2009.
 H. Siomi and M. C. Siomi, "Posttranscriptional regulation of MicroRNA biogenesis in animals," Molecular Cell, vol. 38, no. 3, pp. 323-332, 2010.
 S. Nottrott, M. J. Simard, and J. D. Richter, "Human let7a miRNA blocks protein production on actively translating polyribosomes," Nature Structural and Molecular Biology, vol. 13, no. 12, pp. 1108-1114, 2006.
 R. S. Pilai, S. N. Bhattacharyya, and W. Filipowicz, "Repression of protein synthesis by miRNAs: how many mechanisms?" Trends in Cell Biology, vol. 17, no. 3, pp. 118-126, 2007.
 F. Moretti, R. Thermann, and M. W. Hentze, "Mechanism of translational regulation by miR-2 from sites in the 5' untranslated region or the open reading frame," RNA, vol. 16, no. 12, pp. 2493-2502, 2010.
 D. T. Humphreys, B. J. Westman, D. I. K. Martin, and T. Preiss, "MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 47, pp. 16961-16966, 2005.
 P. H. Olsen and V. Ambros, "The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation," Developmental Biology, vol. 216, no. 2, pp. 671-680,1999.
 C. P Petersen, M.-E. Bordeleau, J. Pelletier, and P A. Sharp, "Short RNAs repress translation after initiation in mammalian cells," Molecular Cell, vol. 21, no. 4, pp. 533-542, 2006.
 E. Bernstein, A. A. Caudy, S. M. Hammond, and G. J. Hannon, "Role for a bidentate ribonuclease in the initiation step of RNA interference," Nature, vol. 409, no. 6818, pp. 363-366, 2001.
 J. Liu, M. A. Carmell, F. V. Rivas et al., "Argonaute2 is the catalytic engine of mammalian RNAi," Science, vol. 305, no. 5689, pp. 1437-1441, 2004.
 Z. Mourelatos, J. Dostie, S. Paushkin et al., "miRNPs: a novel class of ribonucleoproteins containing numerous MicroRNAs," Genes and Development, vol. 16, no. 6, pp. 720-728, 2002.
 Y. Lee, C. Ahn, J. Han et al., "The nuclear RNase III Drosha initiates MicroRNA processing," Nature, vol. 425, no. 6956, pp. 415-419, 2003.
 M. T. Bohnsack, K. Czaplinski, and D. Gorlich, "Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs," RNA, vol. 10, no. 2, pp. 185-191, 2004.
 A. A. Caudy, M. Myers, G. J. Hannon, and S. M. Hammond, "Fragile X-related protein and VIG associate with the RNA interference machinery," Genes and Development, vol. 16, no. 19, pp. 2491-2496, 2002.
 S. W. Knight and B. L. Bass, "The role of RNA editing by ADARs in RNAi," Molecular Cell, vol. 10, no. 4, pp. 809-817, 2002.
 Y. Lee, I. Hur, S.-Y. Park, Y.-K. Kim, R. S. Mi, and V N. Kim, "The role of PACT in the RNA silencing pathway," The EMBO Journal, vol. 25, no. 3, pp. 522-532, 2006.
 L. Weinmann, J. Hock, T. Ivacevic et al., "Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs," Cell, vol. 136, no. 3, pp. 496-507, 2009.
 S. N. Bhattacharyya, R. Habermacher, U. Martine, E. I. Closs, andW. Filipowicz, "Relief of MicroRNA-mediated translational repression in human cells subjected to stress," Cell, vol. 125, no. 6, pp. 1111-1124, 2006.
 M. Kedde, M. J. Strasser, B. Boldajipour et al., "RNA-binding protein Dnd1 inhibits MicroRNA access to target mRNA," Cell, vol. 131, no. 7, pp. 1273-1286, 2007.
 T P Lu, C. Y. Lee, M. H. Tsai et al., "miRSystem: an integrated system for characterizing enriched functions and pathways of MicroRNA targets," PLoS ONE, vol. 7, no. 8, Article ID e42390, 2012.
 B. John, A. J. Enright, A. Aravin, T. Tuschl, C. Sander, and D. S. Marks, "Human MicroRNA targets," PLoS Biology, vol. 2, no. 11, article e363, 2004.
 B. P Lewis, C. B. Burge, and D. P Bartel, "Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are MicroRNA targets," Cell, vol. 120, no. 1, pp. 15-20, 2005.
 A. Krek, D. Griin, M. N. Poy et al., "Combinatorial MicroRNA target predictions," Nature Genetics, vol. 37, no. 5, pp. 495-500, 2005.
 M. Maragkakis, M. Reczko, V. A. Simossis et al., "DIANAMicroT web server: elucidating MicroRNA functions through target prediction," Nucleic Acids Research, vol. 37, supplement 2, pp. W273-W276, 2009.
 P H. Reyes-Herrera, E. Ficarra, A. Acquaviva, and E. Macii, "miREE: miRNA recognition elements ensemble," BMC Bioinformatics, vol. 12, article 454, 2011.
 K. C. Miranda, T. Huynh, Y. Tay et al., "A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes," Cell, vol. 126, no. 6, pp. 1203-1217, 2006.
 T Vergoulis, I. S. Vlachos, P Alexiou et al., "TarBase 6.0: capturing the exponential growth of miRNA targets with experimental support," Nucleic Acids Research, vol. 40, no. D1, pp. D222-D229, 2012.
 S.-D. Hsu, C.-H. Chu, A.-P Tsou et al., "miRNAMap 2.0: genomic maps of MicroRNAs in metazoan genomes," Nucleic Acids Research, vol. 36, supplement 1, pp. D165-D169, 2008.
 H. Naeem, R. Kuffner, G. Csaba, and R. Zimmer, "miRSel: automated extraction of associations between MicroRNAs and genes from the biomedical literature," BMC Bioinformatics, vol. 11, article 135, 2010.
 F. Xiao, Z. Zuo, G. Cai, S. Kang, X. Gao, and T Li, "miRecords: an integrated resource for MicroRNA-target interactions," Nucleic Acids Research, vol. 37, supplement 1, pp. D105-D110, 2009.
 S.-D. Hsu, F.-M. Lin, W.-Y. Wu et al., "miRTarBase: a database curates experimentally validated MicroRNA-target interactions," Nucleic Acids Research, vol. 39, supplement 1, pp. D163D169, 2011.
 H. Dweep, C. Sticht, P Pandey, and N. Gretz, "miRWalk--database: prediction of possible miRNA binding sites by "walking" the genes of three genomes," Journal of Biomedical Informatics, vol. 44, no. 5, pp. 839-847, 2011.
 J.-H. Yang, J.-H. Li, P. Shao, H. Zhou, Y.-Q. Chen, and L.H. Qu, "StarBase: a database for exploring MicroRNA-mRNA interaction maps from Argonaute CLIP-Seq and DegradomeSeq data," Nucleic Acids Research, vol. 39, supplement 1, pp. D202-D209, 2011.
 H. Kim, S. Park, H. Min, and S. Yoon, "vHoT: a database for predicting interspecies interactions between viral MicroRNA and host genomes," Archives of Virology, vol. 157, no. 3, pp. 497-501, 2012.
 J. Huang, C. Townsend, D. Dou, H. Liu, and M. Tan, "OMIT: a domain-specific knowledge base for MicroRNA target prediction," Pharmaceutical Research, vol. 28, no. 12, pp. 3101-3104, 2011.
 Y. Wu, B. Wei, H. Liu, T. Li, and S. Rayner, "miRPara: a SVM-based software tool for prediction of most probable MicroRNA coding regions in genome scale sequences," BMC Bioinformatics, vol. 12, article 107, 2011.
 F. Navarro, D. Gutman, E. Meire et al., "miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53," Blood, vol. 114, no. 10, pp. 2181-2192, 2009.
 A. Ichimura, Y. Ruike, K. Terasawa, K. Shimizu, and G. Tsujimoto, "MicroRNA-34a inhibits cell proliferation by repressing mitogen-activated protein kinase kinase 1 during megakaryocytic differentiation of K562 cells," Molecular Pharmacology, vol. 77, no. 6, pp. 1016-1024, 2010.
 P. Romania, V. Lulli, E. Pelosi, M. Biffoni, C. Peschle, and G. Marziali, "MicroRNA 155 modulates megakaryopoiesis at progenitor and precursor level by targeting Ets-1 and Meis1 transcription factors," British Journal of Haematology, vol. 143, no. 4, pp. 570-580, 2008.
 D. T. Starczynowski, F. Kuchenbauer, B. Argiropoulos et al., "Identification of miR-145 and miR-146a as mediators of the 5qsyndrome phenotype," Nature Medicine, vol. 16, no. 1, pp. 49-58,
 J. B. Opalinska, A. Bersenev, Z. Zhang et al., "MicroRNA expression in maturing murine megakaryocytes," Blood, vol. 116, no. 23, pp. e128-e138, 2010.
 J. Lu, S. Guo, B. L. Ebert et al., "MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors," Developmental Cell, vol. 14, no. 6, pp. 843-853, 2008.
 C. F. Barroga, H. Pham, and K. Kaushansky, "Thrombopoietin regulates c-Myb expression by modulating micro RNA 150 expression," Experimental Hematology, vol. 36, no. 12, pp. 1585-1592, 2008.
 M. Girardot, C. Pecquet, S. Boukour et al., "miR-28 is a thrombopoietin receptor targeting MicroRNA detected in a fraction of myeloproliferative neoplasm patient platelets," Blood, vol. 116, no. 3, pp. 437-445, 2010.
 O. Ben-Ami, N. Pencovich, J. Lotem, D. Levanon, and Y. Groner, "A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 1, pp. 238-243, 2009.
 C. Guimaraes-Sternberg, A. Meerson, I. Shaked, and H. Soreq, "MicroRNA modulation of megakaryoblast fate involves cholinergic signaling," Leukemia Research, vol. 30, no. 5, pp. 583-595, 2006.
 J.-H. Klusmann, Z. Li, K. Bohmer et al., "miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia," Genes and Development, vol. 24, no. 5, pp. 478-490, 2010.
 X. Li, J. Zhang, L. Gao et al., "miR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit," Cell Death and Differentiation, vol. 19, no. 3, pp. 378-386, 2012.
 L. C. Dore, J. D. Amigo, C. O. Dos Santos et al., "A GATA-1-regulated MicroRNA locus essential for erythropoiesis," Proceedings of the National Academy of Sciences of the United States ofAmerica, vol. 105, no. 9, pp. 3333-3338, 2008.
 K. D. Rasmussen, S. Simmini, C. Abreu-Goodger et al., "The miR-144/451 locus is required for erythroid homeostasis," Journal of Experimental Medicine, vol. 207, no. 7, pp. 1351-1358,2010.
 D. M. Patrick, C. C. Zhang, Y. Tao et al., "Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3[zeta]," Genes and Development, vol. 24, no. 15, pp. 1614-1619, 2010.
 A. J. Warren, W. H. Colledge, M. B. L. Carlton, M. J. Evans, A. J. H. Smith, and T. H. Rabbitts, "The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development," Cell, vol. 78, no. 1, pp. 45-57,1994.
 N. Felli, F. Pedini, P. Romania et al., "MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis," Haematologica, vol. 94, no. 4, pp. 479-486, 2009.
 M. L. Choong, H. H. Yang, and I. McNiece, "MicroRNA expression profiling during human cord blood-derived CD34 cell erythropoiesis," Experimental Hematology, vol. 35, no. 4, pp. 551-564, 2007.
 S.-Y. Chen, Y. Wang, M. J. Telen, and J.-T. Chi, "The genomic analysis of erythrocyte MicroRNA expression in sickle cell diseases," PLoS ONE, vol. 3, no. 6, Article ID e2360, 2008.
 N. Felli, L. Fontana, E. Pelosi et al., "MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 50, pp. 18081-18086, 2005.
 Q. Wang, Z. Huang, H. Xue et al., "MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4," Blood, vol. 111, no. 2, pp. 588-595, 2008.
 H. Zhao, A. Kalota, S. Jin, and A. M. Gewirtz, "Autoregulatory feedback loop in human hematopoietic cells the c-myb proto-oncogene and MicroRNA-15a comprise an active," Blood, vol. 113, no. 3, pp. 505-516, 2009.
 Z. Li, J. Lu, M. Sun et al., "Distinct MicroRNA expression profiles in acute myeloid leukemia with common translocations," Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 40, pp. 15535-15540, 2008.
 M. Eyholzer, S. Schmid, J. A. Schardt, S. Haefliger, B. U. Mueller, and T. Pabst, "Complexity of miR-223 regulation by CEBPA in human AML," Leukemia Research, vol. 34, no. 5, pp. 672-676, 2010.
 G. Cammarata, L. Augugliaro, D. Salemi et al., "Differential expression of specific MicroRNA and their targets in acute myeloid leukemia," The American Journal of Hematology, vol. 85, no. 5, pp. 331-339, 2010.
 B. Hackanson, K. L. Bennett, R. M. Brena et al., "Epigenetic modification of CCAAT/enhancer binding protein a expression in acute myeloid leukemia," Cancer Research, vol. 68, no. 9, pp. 3142-3151, 2008.
 M. He, Q. Y. Wang, Q. Q. Yin et al., "HIF-1alpha downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation," Cell Death Differentiation, vol. 20, no. 3, pp. 408-418, 2013.
 R. Garzon, S. Liu, M. Fabbri et al., "MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1," Blood, vol. 113, no. 25, pp. 6411-6418, 2009.
 E. Coskun, E. K. von der Heide, C. Schlee et al., "The role of MicroRNA-196a and MicroRNA-196b as ERG regulators in acute myeloid leukemia and acute T-lymphoblastic leukemia," Leukemia Research, vol. 35, no. 2, pp. 208-213, 2011.
 X.-N. Gao, J. Lin, L. Gao, Y.-H. Li, L.-L. Wang, and L. Yu, "MicroRNA-193b regulates c-Kit proto-oncogene and represses cell proliferation in acute myeloid leukemia," Leukemia Research, vol. 35, no. 9, pp. 1226-1232, 2011.
 L. Venturini, K. Battmer, M. Castoldi et al., "Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells," Blood, vol. 109, no. 10, pp. 4399-4405, 2007
 H. Hu, Y. Li, J. Gu et al., "Antisense oligonucleotide against miR21 inhibits migration and induces apoptosis in leukemic K562 cells," Leukemia and Lymphoma, vol. 51, no. 4, pp. 694-701,2010.
 C. S. Chim, K. Y. Wong, C. Y. Leung et al., "Epigenetic inactivation of the hsa-miR-203 in haematological malignancies," Journal of Cellular and Molecular Medicine, vol. 15, no. 12, pp. 2760-2767, 2011.
 T. Lopotova, M. Zackova, H. Klamova, and J. Moravcova, "MicroRNA-451 in chronic myeloid leukemia: miR-451-BCRABL regulatory loop?" Leukemia Research, vol. 35, no. 7, pp. 974-977, 2011.
 Y. Li, H. Wang, K. Tao et al., "miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein," Experimental Cell Research, vol. 319, no. 8, pp. 1094-1101, 2013.
 C. Xu, H. Fu, L. Gao et al., "BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia," Oncogene, 2012.
 E. Turrini, S. Haenisch, S. Laechelt, T. Diewock, O. Bruhn, and I. Cascorbi, "MicroRNA profiling in K-562 cells under imatinib treatment: influence of miR-212 and miR-328 on ABCG2 expression," Pharmacogenetics and Genomics, vol. 22, no. 3, pp. 198-205, 2012.
 J. Han, Y. Lee, K.-H. Yeom, Y.-K. Kim, H. Jin, and V N. Kim, "The Drosha-DGCR8 complex in primary MicroRNA processing," Genes and Development, vol. 18, no. 24, pp. 3016-3027, 2004.
 J. G. Ruby, C. H. Jan, and D. P. Bartel, "Intronic MicroRNA precursors that bypass Drosha processing," Nature, vol. 448, no. 7149, pp. 83-86, 2007.
 E. Lund, S. Guttinger, A. Calado, J. E. Dahlberg, and U. Kutay, "Nuclear export of MicroRNA precursors," Science, vol. 303, no. 5654, pp. 95-98, 2004.
 T P Chendrimada, R. I. Gregory, E. Kumaraswamy et al., "TRBP recruits the Dicer complex to Ago2 for MicroRNA processing and gene silencing," Nature, vol. 436, no. 7051, pp. 740-744, 2005.
 A. D. Haase, L. Jaskiewicz, H. Zhang et al., "TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing," EMBO Reports, vol. 6, no. 10, pp. 961-967, 2005.
 S. Singh, S. C. Bevan, K. Patil, D. C. Newton, and P A. Marsden, "Extensive variation in the 5;-UTR of Dicer mRNAs influences translational efficiency," Biochemical and Biophysical Research Communications, vol. 335, no. 3, pp. 643-650, 2005.
 D. P Bartel, "MicroRNAs: target recognition and regulatory functions," Cell, vol. 136, no. 2, pp. 215-233, 2009.
 I. Behm-Ansmant, J. Rehwinkel, T. Doerks, A. Stark, P Bork, and E. Izaurralde, "mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes," Genes and Development, vol. 20, no. 14, pp. 1885-1898, 2006.
 E. van Rooij, "The art of MicroRNA research," Circulation Research, vol. 108, no. 2, pp. 219-234, 2011.
 L. F. Sempere, S. Freemantle, I. Pitha-Rowe, E. Moss, E. Dmitrovsky, and V. Ambros, "Expression profiling of mammalian MicroRNAs uncovers a subset of brain-expressed MicroRNAs with possible roles in murine and human neuronal differentiation," Genome Biology, vol. 5, no. 3, article R13, 2004.
 O. Barad, E. Meiri, A. Avniel et al., "MicroRNA expression detected by oligonucleotide Microarrays: system establishment and expression profiling in human tissues," Genome Research, vol. 14, no. 12, pp. 2486-2494, 2004.
 C. Chen, D. A. Ridzon, A. J. Broomer et al., "Real-time quantification of MicroRNAs by stem-loop RT-PCR," Nucleic Acids Research, vol. 33, no. 20, article e179, 2005.
 S. W. Chi, J. B. Zang, A. Mele, and R. B. Darnell, "Argonaute HITS-CLIP decodes MicroRNA-mRNA interaction maps," Nature, vol. 460, no. 7254, pp. 479-486, 2009.
 D. Baek, J. Villaen, C. Shin, F. D. Camargo, S. P. Gygi, and D. P. Bartel, "The impact of MicroRNAs on protein output," Nature, vol. 455, no. 7209, pp. 64-71, 2008.
 J. Vinther, M. M. Hedegaard, P. P. Gardner, J. S. Andersen, and P. Arctander, "Identification of miRNA targets with stable isotope labeling by amino acids in cell culture," Nucleic Acids Research, vol. 34, no. 16, article e107, 2006.
 A. Cimmino, G. A. Calin, M. Fabbri et al., "miR-15 and miR-16 induce apoptosis by targeting BCL2," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 39, pp. 13944-13949, 2005.
 K.-H. Lee, Y.-L. Chen, S.-D. Yeh et al., "MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation," Oncogene, vol. 28, no. 38, pp. 3360-3370, 2009.
 J. A. Chan, A. M. Krichevsky, and K. S. Kosik, "MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells," Cancer Research, vol. 65, no. 14, pp. 6029-6033, 2005.
 V. Plaisance, A. Abderrahmani, V Perret-Menoud, P Jacquemin, F. Lemaigre, and R. Regazzi, "MicroRNA-9 controls the expression of Granuphilin/Slp4 and the secretory response of insulin-producing cells," Journal of Biological Chemistry, vol. 281, no. 37, pp. 26932-26942, 2006.
 T. Melkman-Zehavi, R. Oren, S. Kredo-Russo et al., "miRNAs control insulin content in pancreatic ^-cells via downregulation of transcriptional repressors," The EMBO Journal, vol. 30, no. 5, pp. 835-845, 2011.
 C. Esau, S. Davis, S. F. Murray et al., "miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting," Cell Metabolism, vol. 3, no. 2, pp. 87-98, 2006.
 J. Elmen, M. Lindow, A. Silahtaroglu et al., "Antagonism of MicroRNA-122 in mice by systemically administered LNAantimiR leads to up-regulation of a large set of predicted target mRNAs in the liver," Nucleic Acids Research, vol. 36, no. 4, pp. 1153-1162, 2008.
 K. J. Rayner, F. J. Sheedy, C. C. Esau et al, "Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis," Journal of Clinical Investigation, vol. 121, no. 7, pp. 2921-2931, 2011.
 K. J. Rayner, Y. Suarez, A. Davalos et al., "miR-33 contributes to the regulation of cholesterol homeostasis," Science, vol. 328, no. 5985, pp. 1570-1573, 2010.
 R. W. Georgantas III, R. Hildreth, S. Morisot et al., "CD34+ hematopoietic stem-progenitor cell MicroRNA expression and function: a circuit diagram of differentiation control," Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 8, pp. 2750-2755, 2007
 A. Marson, S. S. Levine, M. F. Cole et al., "Connecting MicroRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells," Cell, vol. 134, no. 3, pp. 521-533, 2008.
 C.-Z. Chen, L. Li, H. F. Lodish, and D. P. Bartel, "MicroRNAs modulate hematopoietic lineage differentiation," Science, vol. 303, no. 5654, pp. 83-86, 2004.
 S. B. Koralov, S. A. Muljo, G. R. Galler et al., "Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage," Cell, vol. 132, no. 5, pp. 860-874, 2008.
 X. Liu, Z. Zhan, L. Xu et al., "MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIa," The Journal of Immunology, vol. 185, no. 12, pp. 7244-7251, 2010.
 C.-P. Mao, L. He, Y.-C. Tsai et al., "In vivo MicroRNA-155 expression influences antigen-specific T cell-mediated immune responses generated by DNA vaccination," Cell and Bioscience, vol. 1, no. 1, article 3, 2011.
 E. Bernstein, S. Y. Kim, M. A. Carmell et al., "Dicer is essential for mouse development," Nature Genetics, vol. 35, no. 3, pp. 215-217, 2003.
 B. S. Cobb, T B. Nesterova, E. Thompson et al., "T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer," Journal of Experimental Medicine, vol. 201, no. 9, pp. 1367-1373, 2005.
 K. D. Taganov, M. P. Boldin, K.-J. Chang, and D. Baltimore, "NFxB-dependent induction of MicroRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses," Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 33, pp. 12481-12486, 2006.
 C. Labbaye, I. Spinello, M. T. Quaranta et al., "A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis," Nature Cell Biology, vol. 10, no. 7, pp. 788-801, 2008.
 R. Garzon, F. Pichiorri, T. Palumbo et al., "MicroRNA fingerprints during human megakaryocytopoiesis," Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 13, pp. 5078-5083, 2006.
 I. Azzouzi, H. Moest, J. Winkler et al., "Microrna-96 directly inhibits y-globin expression in human erythropoiesis," PLoS ONE, vol. 6, no. 7, Article ID e22838, 2011.
 R. J. Mayoral, L. Deho, N. Rusca et al., "miR-221 influences effector functions and actin cytoskeleton in mast cells," PLoS ONE, vol. 6, no. 10, Article ID e26133, 2011.
 T. Ishizaki, T. Tamiya, K. Taniguchi et al., "miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1," Genes to Cells, vol. 16, no. 7, pp. 803-814, 2011.
 R. J. Mayoral, M. E. Pipkin, M. Pachkov, E. van Nimwegen, A. Rao, and S. Monticelli, "MicroRNA-221-222 regulate the cell cycle in mast cells," The Journal of Immunology, vol. 182, no. 1, pp. 433-445, 2009.
 E. Surdziel, M. Cabanski, I. Dallmann et al., "Enforced expression of miR-125b affects myelopoiesis by targeting multiple signaling pathways," Blood, vol. 117, no. 16, pp. 4338-4348, 2011.
 F. Fazi, S. Racanicchi, G. Zardo et al., "Epigenetic silencing of the myelopoiesis regulator MicroRNA-223 by the AML1/ETO oncoprotein," Cancer Cell, vol. 12, no. 5, pp. 457-466, 2007
 A. Ventura, A. G. Young, M. M. Winslow et al., "Targeted deletion reveals essential and overlapping functions of the miR17~92 family of miRNA clusters," Cell, vol. 132, no. 5, pp. 875886, 2008.
 C. S. Velu, A. M. Baktula, and H. L. Grimes, "Gfi1 regulates miR21 and miR-196b to control myelopoiesis," Blood, vol. 113, no. 19, pp. 4720-4728, 2009.
 E. Tenedini, E. Roncaglia, F. Ferrari et al., "Integrated analysis of MicroRNA and mRNA expression profiles in physiological myelopoiesis: role ofhsa-miR-299-5p in CD34+ progenitor cells commitment," Cell Death and Disease, vol. 1, no. 2, article e28, 2010.
 S. Kuchen, W. Resch, A. Yamane et al., "Regulation of MicroRNA expression and abundance during lymphopoiesis," Immunity, vol. 32, no. 6, pp. 828-839, 2010.
 J. Mattes, A. Collison, M. Plank, S. Phipps, and P. S. Foster, "Antagonism of MicroRNA-126 suppresses the effector function of T H2 cells and the development of allergic airways disease," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 44, pp. 18704-18709, 2009.
 A. Collison, J. Mattes, M. Plank, and P. S. Foster, "Inhibition of house dust mite-induced allergic airways disease by antagonism of MicroRNA-145 is comparable to glucocorticoid treatment," Journal of Allergy and Clinical Immunology, vol. 128, no. 1, pp. 160-167, 2011.
 F. Allantaz, D. T. Cheng, T. Bergauer et al., "Expression profiling of human immune cell subsets identifies miRNAmRNA regulatory relationships correlated with cell type specific expression," PLoS ONE, vol. 7, no. 1, Article ID e29979, 2012.
 C. K. Wong, K. M. Lau, I. H. S. Chan et al., "MicroRNA21* regulates the prosurvival effect of GM-CSF on human eosinophils," Immunobiology, vol. 218, no. 2, pp. 255-262, 2013.
 J. Batliner, E. Buehrer, E. A. Federzoni et al., "Transcriptional regulation of miR29B by PU.1 (SPI1) and MYC during neutrophil differentiation of acute promyelocytic leukaemia cells," British Journal of Haematology, vol. 157, no. 2, pp. 270-274,2012.
 J. B. Johnnidis, M. H. Harris, R. T. Wheeler et al., "Regulation of progenitor cell proliferation and granulocyte function by MicroRNA-223," Nature, vol. 451, no. 7182, pp. 1125-1129, 2008.
 J. R. Ward, P. R. Heath, J. W. Catto, M. K. B. Whyte, M. Milo, and S. A. Renshaw, "Regulation of neutrophil senescence by MicroRNAs," PLoS ONE, vol. 6, no. 1, Article ID e15810, 2011.
 F. Bazzoni, M. Rossato, M. Fabbri et al., "Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 13, pp. 5282-5287, 2009.
 T. Zhong, J. M. Perelman, V P. Kolosov, and X.-D. Zhou, "miR-146a negatively regulates neutrophil elastase-induced MUC5AC secretion from 16HBE human bronchial epithelial cells," Molecular and Cellular Biochemistry, vol. 358, no. 1-2, pp. 249-255, 2011.
 B. Izumi, T. Nakasa, N. Tanaka et al., "MicroRNA-223 expression in neutrophils in the early phase of secondary damage after spinal cord injury," Neuroscience Letters, vol. 492, no. 2, pp. 114-118, 2011.
 S. Slezak, P. Jin, L. Caruccio et al., "Gene and MicroRNA analysis of neutrophils from patients with polycythemia vera and essential thrombocytosis: down-regulation of MicroRNA-1 and -133a," Journal of Translational Medicine, vol. 7, article 39, 2009.
 S. Radom-Aizik, F. Zaldivar Jr., S. Oliver, P Galassetti, and D. M. Cooper, "Evidence for MicroRNA involvement in exercise-associated neutrophil gene expression changes," Journal of Applied Physiology, vol. 109, no. 1, pp. 252-261, 2010.
 C. Schmelzer, M. Kitano, G. Rimbach et al., "Effects of ubiquinol-10 on MicroRNA-146a expression in vitro and in vivo," Mediators of Inflammation, vol. 2009, Article ID 415-437, 7 pages, 2009.
 M. Etzrodi, V. Cortez-Retamozo, A. Newton et al., "Regulation of monocyte functional heterogeneity by miR-146aand Relb," Cell Reports, vol. 1, no. 4, pp. 317-324, 2012.
 K. M. Pauley, C. M. Stewart, A. E. Gauna et al., "Altered miR146a expression in Sjogren's syndrome and its functional role in innate immunity," European Journal of Immunology, vol. 41, no. 7, pp. 2029-2039, 2011.
 E. Cocco, F. Paladini, G. Macino, V. Fulci, M. T. Fiorillo, and R. Sorrentino, "The expression of vasoactive intestinal peptide receptor 1 is negatively modulated by MicroRNA 525-5p," PLoS ONE, vol. 5, no. 8, Article ID e12067, 2010.
 A. T. Conrad and B. N. Dittel, "Taming of macrophage and Microglial cell activation by MicroRNA-124," Cell Research, vol. 21, no. 2, pp. 213-216, 2011.
 E. Tili, J.-J. Michaille, B. Adair et al., "Resveratrol decreases the levels of miR-155 by upregulating miR-663, a MicroRNA targeting JunB and JunD," Carcinogenesis, vol. 31, no. 9, pp. 1561-1566, 2010.
 S. Sharbati, J. Sharbati, L. Hoeke, M. Bohmer, and R. Einspanier, "Quantification and accurate normalisation of small RNAs through new custom RT-qPCR arrays demonstrates Salmonella-induced MicroRNAs in human monocytes," BMC Genomics, vol. 13, no. 1, article 23, 2012.
 H. Wu, J. R. Neilson, P Kumar et al., "miRNA profiling of naive, effector and memory CD8 T cells," PLoS ONE, vol. 2, no. 10, Article ID e1020, 2007.
 R. Sandberg, J. R. Neilson, A. Sarma, P A. Sharp, and C. B. Burge, "Proliferating cells express mRNAs with shortened 3; untranslated regions and fewer MicroRNA target sites," Science, vol. 320, no. 5883, pp. 1643-1647, 2008.
 B. S. Cobb, A. Hertweck, J. Smith et al., "A role for Dicer in immune regulation," Journal of Experimental Medicine, vol. 203, no. 11, pp. 2519-2527, 2006.
 A. Liston, L.-F. Lu, D. O'Carroll, A. Tarakhovsky, and A. Y. Rudensky, "Dicer-dependent MicroRNA pathway safeguards regulatory T cell function," Journal of Experimental Medicine, vol. 205, no. 9, pp. 1993-2004, 2008.
 T. M. Laufer, "T-cell sensitivity: a MicroRNA regulates the sensitivity of the T-cell receptor," Immunology and Cell Biology, vol. 85, no. 5, pp. 346-347, 2007
 E. L. Virts and M. L. Thoman, "Age-associated changes in miRNA expression profiles in thymopoiesis," Mechanisms of Ageing and Development, vol. 131, no. 11-12, pp. 743-748, 2010.
 M. Ohyashiki, J. H. Ohyashiki, A. Hirota, C. Kobayashi, and K. Ohyashiki, "Age-related decrease of miRNA-92a levels in human CD8+ T-cells correlates with a reduction of naive T lymphocytes," Immunity & Ageing, vol. 8, article 11, 2011.
 J. Li, Y. Wan, Q. Guo et al., "Altered MicroRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis," Arthritis Research & Therapy, vol. 12, no. 3, article R81, 2010.
 G. Almanza, A. Fernandez, S. Volinia, X. Cortez-Gonzalez, C. M. Croce, and M. Zanetti, "Selected MicroRNAs define cell fate determination of murine central memory CD8 T cells," PLoS ONE, vol. 5, no. 6, Article ID el1243, 2010.
 L. P Tan, M. Wang, J.-L. Robertus et al., "miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes," Laboratory Investigation, vol. 89, no. 6, pp. 708-716, 2009.
 C. Xiao, D. P Calado, G. Galler et al., "miR-150 controls B cell differentiation by targeting the transcription factor c-Myb," Cell, vol. 131, no. 1, pp. 146-159, 2007.
 E. Vigorito, K. L. Perks, C. Abreu-Goodger et al., "Micro-RNA155 regulates the generation of immunoglobulin class-switched plasma cells," Immunity, vol. 27, no. 6, pp. 847-859, 2007
 G. A. Calin, C. D. Dumitru, M. Shimizu et al., "Frequent deletions and down-regulation of Micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 24, pp. 15524-15529, 2002.
 "Cancer Facts & Figures 2012," 2012, http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/ cancer-facts.
 S. Faderl, M. Talpaz, Z. Estrov, and H. M. Kantarjian, "Chronic myelogenous leukemia: biology and therapy," Annals of Internal Medicine, vol. 131, no. 3, pp. 207-219,1999.
 O. H. Rokah, G. Granot, A. Ovcharenko et al., "Downregulation of miR-31, miR-155, and miR-564 in chronic myeloid leukemia cells," PLoS ONE, vol. 7, no. 4, Article ID e35501, 2012.
 K. Machova Polakova, T. Lopotova, H. Klamova et al., "Expression patterns of MicroRNAs associated with CML phases and their disease related targets," Molecular Cancer, vol. 10, article 41, 2011.
 J. Fei, Y. Li, X. Zhu, and X. Luo, "miR-181a post-transcriptionally downregulates oncogenic rala and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML)," PLoS ONE, vol. 7, no. 3, Article ID e32834, 2012.
 S. Suresh, L. McCallum, W. Lu, N. Lazar, B. Perbal, and A. E. Irvine, "MicroRNAs 130a/b are regulated by BCR-ABL and downregulate expression of CCN3 in CML," Journal of Cell Communication and Signaling, vol. 5, no. 3, pp. 183-191, 2011.
 K. Bommert, R. C. Bargou, and T. Stuhmer, "Signalling and survival pathways in multiple myeloma," European Journal of Cancer, vol. 42, no. 11, pp. 1574-1580, 2006.
 A. Mahindra, T. Hideshima, and K. C. Anderson, "Multiple myeloma: biology of the disease," Blood Reviews, vol. 24, supplement 1, pp. S5-S11, 2010.
 R. A. Kyle and S. V. Rajkumar, "Multiple myeloma," Blood, vol. 111, no. 6, pp. 2962-2972, 2008.
 S. L. Corthals, S. M. Sun, R. Kuiper et al., "MicroRNA signatures characterize multiple myeloma patients," Leukemia, vol. 25, no. 11, pp. 1784-1789, 2011.
 C. I. Jones, M. V. Zabolotskaya, A. J. King et al., "Identification of circulating MicroRNAs as diagnostic biomarkers for use in multiple myeloma," British Journal of Cancer, vol. 107, no. 12, pp. 1987-1996, 2012.
 Y. Zhou, L. Chen, B. Barlogie et al., "High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2," Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 17, pp. 7904-7909, 2010.
 A. M. Roccaro, A. Sacco, B. Thompson et al., "MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma," Blood, vol. 113, no. 26, pp. 6669-6680, 2009.
 S. L. Corthals, M. Jongen-Lavrencic, Y. de Knegt et al., "MicroRNA-15a and Micro-RNA-16 expression and chromosome 13 deletions in multiple myeloma," Leukemia Research, vol. 34, no. 5, pp. 677-681, 2010.
 L. Chen, C. Li, R. Zhang et al., "miR-17-92 cluster MicroRNAs confers tumorigenicity in multiple myeloma," Cancer Letters, vol. 309, no. 1, pp. 62-70, 2011.
 Y.-K. Zhang, H. Wang, Y. Leng et al., "Overexpression of MicroRNA-29b induces apoptosis of multiple myeloma cells through down regulating Mcl-1," Biochemical and Biophysical Research Communications, vol. 414, no. 1, pp. 233-239, 2011.
 K. Unno, Y. Zhou, T. Zimmerman, L. C. Platanias, and A. Wickrema, "Identification of a novel MicroRNA cluster miR193b-365 in multiple myeloma," Leukemia and Lymphoma, vol. 50, no. 11, pp. 1865-1871, 2009.
 S. Adamia, H. Avet-Loiseau, S. B. Amin et al., "Clinical and biological significance of MicroRNA profiling in patients with myeloma," Journal of Clinical Oncology, vol. 27, supplement 15, p. 8539, 2009.
 X. Gao, R. Zhang, X. Qu et al., "miR-15a, miR-16-1 and miR-1792 cluster expression are linked to poor prognosis in multiple myeloma," Leukemia Research, vol. 36, no. 12, pp. 1505-1509, 2012.
 J. Chi, E. Ballabio, X.-H. Chen et al., "MicroRNA expression in multiple myeloma is associated with genetic subtype, isotype and survival," Biology Direct, vol. 6, article 23, 2011.
Ram Babu Undi, Ravinder Kandi, and Ravi Kumar Gutti
Hematologic Oncology, Stem Cells and Blood Disorders Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, Andhra Pradesh 500046, India
Correspondence should be addressed to Ravi Kumar Gutti; email@example.com
Received 30 July 2013; Revised 20 October 2013; Accepted 27 October 2013
Academic Editor: Aldo Roccaro
Table 1: miRNA nomenclature. Notation Description Species name (Homo sapiens) "hsa" (Eg. hsa-miR-21) Eg. Mmu--mus musculus rno--Rattus norvegicus cel-- Caenorhabditis elegans ath-- Arabidopsis thalianadme-Drosophila melanogaster "miR" (Eg. hsa-mir-17) Denotes immature form of miRNA (pre-miRNA) or primary transcript or genomic locus "miR" (Eg. has-miR-10) Refers to the mature form of miRNA a and b notation (Eg. When two miRNAs are similar except miR-147a, miR-147b) in 2 or 3 nt, then they are denoted by lowercased letters Additional numbers in In case of two miRNAs are 100% names (Eg. miR-16-1, similar, but they are located on miR-16-2) different chromosomes and then they are denoted by extra dash followed by number "*" notation (Eg. If the same precursor miRNA produces miR-56/ miR-56*) two miRNAs, then the less predominant one is denoted by * 3p- and 5p- notation (Eg. If the data is not sufficient to know miR-56-3p, miR-56-5p) which one is predominant, then it is written as 3p- or 5p-. 3p- and 5p- indicate that it is derived from 3;, 5' arms, respectively. TABLE 2: Proteins involved in miRNA biogenesis. Gene Description Location Function Dicer Dicer 1, 14q31 miRNA processing ribonuclease type II AGO3 Argonaute 3 1p34-p34 Short-interfering- RNA-mediated gene silencing Gemin3 DEAD 1p13.2 RNA helicase (Asp-Glu-Ala-Asp) box polypeptide 20 Drosha Drosha, 5p14-p13 Pri-miRNA ribonuclease processing type II Exportin-5 Karyopherin family 6p21.1 Transport of small RNAs FMRP Fragile X mental Xq27.3 mRNA trafficking retardation 1 ADAR Adenosine 1q21.3 RNA and miRNA deaminase, editing RNA-specific TRBP TAR (HIV-1) RNA 12q12, q-13 Dicer binding protein stabilization Importin-8 GTPase Ran mediate 12p11.21 Nuclear nuclear import localization of Argonaute proteins ELAV1 (Embryonic lethal, 19p13.2 Repression of abnormal vision, target sites Drosophila-like 1) Inhibiting Dndl Dead end homolog 1 5q31.3 miRNA-mediated repression Gene Domains Reference Dicer Type 111 restriction  enzyme, RNase3, DEAH, helicase, dsRBD, PAZ AGO3 PAZ, PIWI, DUF1785,  DUF2344, DUF2678 Gemin3 DEAD, Type 111  restriction enzyme, helicase C Drosha RNase3 domain,  Double-stranded RNA binding motif Exportin-5 Importin-beta  N-terminal domain, exportin 1-like protein FMRP KH domain  ADAR z-Alpha, Dsrm,  Editase TRBP DZF, dsRBD  Importin-8 Cse1  ELAV1 RBD  Dndl PMP-22  TABLE 3: miRNA target prediction tools. Database Description URL miRSystem Predict the target http://mirsystem.cgm. genes and pathways ntu.edu.tw/ miRanda Predict targets by http://www.microrna.org finding high complementarity regions in 3'UTR Detect target genes http://www.targetscan.org by perfect complementarity to the seed region PicTar Seed match, binding http://pictar.mdc- energy, conservation berlin.de/ DIANA-microT Based on affinity http://diana.cslab.ece. interaction between ntua.gr/ miRNA and mRNA Based on miRNA; mRNA http://didattica-online. TABLE 4: miRNA involved in megakaryopoiesis. miRNA Function Putative Reference targets miR-34a MK differentiation of HMGN4, CCDC52, [42, 43] K562 cells, targets cMyb, KLRK1, RGS17, CDKs, and MEK1 nfatcg miR-155 Downregulated in MMP16, SLC11A2,  megakaryopoiesis, targets C2orf18 Meis-1 and Ets-1 miR-146a, Involved in SOX11, SP1  miR-145 megakaryopoiesis by activating innate immunity and mediates 5q syndrome phenotype miR-146a Increased in MK CREBL2, NOTCH2, [46, 47] development and targets TRAK2, TBX18, CXCR4 RIN2, RAD23B, SLC1A2 miR-150 Favours megakaryocyte SLC24A4 [47, 48] lineage differentiation; it targets cMyb, induced by TPO miR-28 It targets TPO receptor  and prevents MK differentiation from [CD34.sup.+] cells miR-27a miR-27a targets and TRIM9, CYB5B,  decrease RUNX1 levels EGR2, BASP1 miR-181a miR-181a inhibit  [Ca.sup.2+] induced differentiation of MKs miR-125b-2 Induces proliferation and RAD98, ZNF100,  differentiation of MKs PDS5B, SHE, CDR2 miR-181 Mediates MK FOXP1, CCN8,  differentiation by HOXA1 disrupting LIN28/let-7 axis TABLE 5: miRNAs involved in erythropoiesis. MiRNA Function Putative Reference targets miR-144, Erythroid homeostasis, TSPAN12, HMGCR, [54, 55] miR-451 deficiency leads to FBN2, MAP3K8, splenomegaly, mild anaemia, CXCL16, EREG, and erythroid hyperplasia, ATF2, CDKN2B controlled by GATA1 miR-451 Erythroid differentiation CDKN2B, CXCL16,  defect and reduction in EREG, ATF2 haematocrit in [miRNA-451.sup.-/-] mice miR-223 Reduces the commitment of LIN54, FOXO1, [57, 58] erythroid progenitors USP42, ALCAM, BCLAF1, SLC11A2 miR-15b, Positive correlation with PRDM4, KIF1B, [59, 60] mi16, erythroid markers CD36, LAMP3, SWAP70, miR-22 CD235a, and CD71 LIN7C, AKT3, LAMC1 miR-28 Negatively correlate with [59, 60] CD71 miR-320 Favours CD71 transcriptional  activities miR-221, Inhibit normal TAF9B, MYLIP,  miR-222 erythropoiesis RAB18, CYP7A1, KIF16B, MAT2A, NXN miR-24 Targets ALK4 TRIB3, CBX5,  KCNJ2, DGA52 miR-15a Transition from BFU-E to GFAP, SLC9A8,  CFU-E stage ZNRF2, FAM81A TABLE 6: miRNAs involved in AML. miRNA Function Putative targets Reference miR-126 * Upregulation ADAT2,FOF1,  leads to LMO7, chromosomal translocations and inhibits apoptosis miR-126 Targets tumour TOM1, CKMT2,  suppressor PLK2 ZNF131, RGS3, miR-223 C/EBP[alpha] ANKH, SCN1A, regulates its SCN3A, CBFB,  expression in CDH11, NEBL, turn it RILPL1, CENPN inhibits E2F1 in AML cells miR-221 Oncogenic HIPK1, RAB18,  miRNA, it DNM3, ZNF547, inhibits the CDK inhibitor p27 miR-124a Target the C/  EBPa, silenced and block differentiation gives leukemia phenotype miR-20a Inhibits the POLQ, KLF12,  and p21 STK38, CENTD1, miR-17 NUP35, GNB5, CTSK miR-29b Tumour SCML2, C1orf96,  suppressor in COL3A1, COL7A1, AML and reduce COL11A1 tumorigenicity miR-29b Reduced CD93, HBP1,  expression of SNX21, GNS, DNA HMGCR, HNF4G, methyltransferases DNMT3B miR-196a They target ERG FOS, GATA6,  and expression HOXB6, HOXC8, miR-196b ZNF24, CCDC47 miR-193b Downregulated MMP19, ARMC1,  in AML and it ARPC5 targets c-Kit TABLE 7: miRNAs involved in CML. miRNA Function Putative targets Reference miR-17-92 Down-regulated in IRF9, RAB10,  imatinib treated TXNIP, TET2 CML cells miR-21 Antisense TXPAN2, LUM,  inhibition leads SUZ12, MSH2, to inhibition of PDZD2 migration and cell growth and induces apoptosis miR-203 Methylated in AML, RTKN2, AAK1,  CML, ALL, CLL. MYST4 CD109, Inhibit the IL21, PLD2 expression of BCR-ABL miR-451 Associated with TSC1, ACADSB,  Bcr-Abl GRSF1, MAML1, GDI1, NAMPT miR-29b Inhibits ABL1 and HAS3, SNX24, BCR/ABL1 there by CD93, SCML2,  inhibiting cell COL7A1, ZNF396, growth and colony HMGCR, ICOS formation miR-138 Represses BCR/ABL1 KLF12, H3F3B,  and CCND3, MYO5C, NXN, NEBL, increases by GATA1 PDPN, STK38 miR-212 Increases the APAF1, EP300,  ABCG2 expression EDNRA, CFL2, NOS1, SOX4, SOX11
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|Author:||Undi, Ram Babu; Kandi, Ravinder; Gutti, Ravi Kumar|
|Publication:||Advances in Hematology|
|Date:||Jan 1, 2014|
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